Premalignant oral lesions have increased levels of Th17 cells, which are replaced with Treg as lesions become head and neck squamous cell carcinomas (HNSCC). This study aims to prevent progression of premalignant lesions to HNSCC by capitalizing on the anti-tumor effects of Th17 cells. The hypothesis of this study is that sustained stimulation of reactivity mediated b IFN-?-expressing Th17 cells in premalignant oral lesions can promote immunological defenses against premalignant lesions and, consequently, prevent HNSCC. The premise of this hypothesis is that Th17 cells can be potent producers of IFN-?, exhibit antigen-specific activity, and recruit dendritic cells and Th1 T-cells. Also, our studies have shown (i) levels of IFN-?-expressing Th17 cells are increased in premalignant lesions, but are replaced with Treg during progression toward HNSCC, (ii) media conditioned by HNSCC skews the Th17 phenotype of cells from mice with premalignant lesions to a Treg phenotype, but IL-23 lessens the loss of Th17 cells, while neutralization of TGF? prevents development of Treg, (iii) inhibition of inflammation exacerbates lesion development. Our hypothesis will be tested in a carcinogen-induced mouse model in which premalignant oral lesions progress into HNSCC. In addition, studies will transition to assessing reactivity of Th17 cells from patients having premalignant oral lesions against autologous lesions. The following aims will test if sustaining the Th17 phenotype can result in protective immune activity against progression of premalignant lesions to HNSCC: 1. To sustain the Th17- IFN-? + cell phenotype as premalignant oral lesions progress toward HNSCC so as to stimulate lesion-specific immune reactivity and reduce progression to malignancy. a. Determine if sustaining the Th17 phenotype by stabilizing Th17 cells with IL-23 and/or preventing skewing toward Treg cells with a TGF-? receptor inhibitor sustains levels of IFN-? -producing Th17 cells with specificity toward premalignant lesions and HNSCC. b. Determine if stabilizing the Th17- IFN-? + phenotype stimulates immune infiltration that is reactive toward premalignant lesions and against the development of HNSCC. 2. To determine the extent to which Th17 cells from patients bearing premalignant oral lesions exhibit specificity toward autologous lesions and whether this activity can be further stimulated with peptides derived from tumor antigens that are prominently expressed on premalignant lesions and HNSCC. The proposed studies are expected to show that the Th17+ IFN-? + phenotype can promote protective immunity against premalignant oral lesions. Since a high proportion of premalignant oral lesions progress to HNSCC, protective immunity against lesions is expected to translate into reduced development of HNSCC.